Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The α7 nAChR is one receptor system that has proved to be a difficult target for testing. Native α7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68(5):2140-51). Another feature that makes functional assays of α7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the α7 nAChR (Eisele et al., Nature, 366(6454), 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the α7 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the α7 nAChR is a calcium channel while the 5-HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken α7 nAChR/mouse 5-HT3R behaves quite differently than the native α7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
U.S. patent application No. 2002/0016334 discloses a pharmaceutical composition for the treatment of attention deficit hyperactivity disorder.
U.S. Pat. No. 6,441,049 B2 disclsoes a method of treating nerodegenerative disorders via inhibition of amyloid beta peptide binding.
U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamic acids useful in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of intermediates in synthesis.
U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the α7 receptor subtype with little or no activation of the α4β2 or other receptor subtypes.
U.S. Pat. No. 5,830,902 discloses quinuclidine derivatives having tricyclic hetero condensed ring. The compounds are disclosed as having strong squalene synthase inhibiting activity and being useful as a cholesterol lowering agent without causing side effects.
U.S. Pat. No. 5,576,434 discloses a novel process for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one, the pharmaceutically acceptable salts thereof, which are 5-HT3 receptor antagonists, and the intermediates thereof.
U.S. Pat. No. 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic, acid ester or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
U.S. Pat. No. 5,434,161 discloses imidazopyridines as serotonergic 5-HT3 antagonists.
U.S. Pat. No. 5,362,740 discloses dihydrobenzofuran carboxamides useful in treating CNS disorders, but motility disorders, and/or emisis and/or pain in mammals, and/or migraine.
U.S. Pat. No. 5,185,333 discloses benzazine compounds useful as drugs for the prophylaxis or treatment of various digestive diseases vomiting and disturbances in central nervous systems and the like.
U.S. Pat. No. 5,175,173 discloses carboxamides useful as antiemetic or antipsychotic agents.
U.S. Pat. No. 5,122,528 discloses analgesic use of benzobicyclic carboxamides.
U.S. Pat. No. 5,114,947 discloses method for alleviating anxiety using benxobicyclic carboxamides.
U.S. Pat. No. 5,039,680 discloses 5-HT3 antagonists in preventing or reducing dependency on dependency-inducing agents.
U.S. Pat. No. 4,983,600 discloses heterocyclic compounds useful as 5-HT3 antagonists.
U.S. Pat. No. 4,935,511 discloses benzoxazine and benzoxazepin carboxamide 5-HT3 antagonists properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D2 receptor binding affinity.
U.S. Pat. No. 4,933,445 discloses heteroazabenzobicyclic carboxamide 5-HT3 antagonists properties including CNS, anti-emetic and gastric prokinetic activity.
U.S. Pat. No. 4,924,010 discloses benzoxepins as intermediates to 5-HT3 antagonists having CNS and gastric prokinetic activity and void of any significant D2 receptor binding properties.
U.S. Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT3 antagonists.
U.S. Pat. No. 4,920,227 discloses benzobicyclic carboxamide 5-HT3 antagonists.
U.S. Pat. No. 4,920,219 discloses substituted saturated and unsaturated indole quinoline and benzazepine carboxamides and their valuable use as 5-HT3 antagonists having CNS and gastric prokinetic activity void of any significant D2 receptor binding properties.
U.S. Pat. No. 4,910,193 discloses treatment of gastrointestinal disorders.
U.S. Pat. No. 4,892,872 discloses benzoxazine compounds exhibiting 5-HT3 receptor antagonistic activity and being useful as antiemetics and so on.
U.S. Pat. No. 4,863,921 discloses dibenzofurancarboxamides and their use as 5-HT3 antagonists having unique CNS, anti-emetic and gastric prokinetic activity void of any significant D2 receptor binding properties.
U.S. Pat. No. 4,857,517 discloses certain specific substituted 9-N-(1-azabicyclo-[2.2.2]octan-3-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepins and their valuable use as 5-HT3 antagonists having CNS and gastric prokinetic activity and void of any significant D2 receptor binding properties.
U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
U.S. Pat. No. 4,803,199 discloses pharmaceutically useful heterocyclic acid esters and amides or alkylene bridged peperidines as serotonin M antagonists.
U.S. Pat. No. 4,797,406 discloses amides and esters containing bridged piperidines and use as serotonin M antagonists.
U.S. Pat. No. 4,721,720 discloses a method of treating emesis, anxiety and/or irritable bowel syndrome.
U.S. Pat. No. 4,612,319 discloses bridged quinolizinidinylamides, compositions containing them and methods for their use.
U.S. Pat. No. 4,605,652 discloses a method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes, and the pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof.
WO 01/76576 A2 discloses a pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines.
WO 01/60821 A1 discloses novel biarylcarboxamides and their use in therapy, especially in the treatement of prophylaxis of psychotic and intellectual impairment conditions.
WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the α7 nAChR and the 5-HT3R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the α7 nAChR.
WO 96/33186 discloses substituted dihydrobenzofuran derivatives as 5-HT4 agonists.
WO 93/06108 discloses pyrrolobenzoxanie derivatives as 5-HT agonists and antagonists.
WO 92/10494 discloses novel compounds that are 5-HT3 receptor antagonists.
WO 91/09593 discloses 5-HT3 antagonists for treatment of nausea, bradycardia or hypotension associated myocardial instability.
EP 496 064 A1 discloses a process for the preparation of substituted benzofuran derivatives. The compounds are disclosed as being useful 5-HT3 receptor antagonists.
In Bioorg. & Med. Chem. Lett. 11 (2001) 319-321, the 5-HT3 antagonist tropisetron (ICS 205-930) is discussed as a potent and selective α7 nicotinic receptor partial agonist.
In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that the brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease using DMXBA which is known as GTS-21.